Archive | Epidemiology RSS feed for this section

Recent autism abstracts in Pubmed

17 Dec

Pubmed is an amazing resource. It is a Public Medical library of abstracts (and some articles) in the medical literature. I have a search set up so that I get emails with recent articles with the subject “autism”. I try to obtain some of the articles and discuss them here. This is not based on what I perceive to be the “best” or “most important” work, just what I want to explore. It has been difficult lately to go into depth in any articles and I find myself falling behind. For example, a couple of days ago the pubmed email had 29 abstracts in one day. Given that, here are a few recent abstracts that caught my eye:

Neonatally measured immunoglobulins and risk of autism.

Grether JK, Croen LA, Anderson MC, Nelson KB, Yolken RH.

California Department of Public Health, Richmond, California.
Abstract

Previous studies indicate that prenatal exposure to infections is a possible pathway through which autism spectrum disorders (ASD) could be initiated. We investigated whether immunoglobulin levels in archived specimens obtained from newborns subsequently diagnosed with ASD are different from levels in newborn specimens from controls. Children with ASD born in six California counties in 1994 were ascertained through records of the California Department of Developmental Services (DDS) and Kaiser Permanente; controls were randomly selected using birth certificates. Archived newborn blood specimens were obtained from the California Genetic Disease Screening Program (GDSP) for N = 213 cases and N = 265 controls and assayed to determine levels of total IgG, antigen-specific IgG to selected common pathogens, total IgM, total IgA, and C-reactive protein (CRP). We did not find measurable levels of total IgM or IgA in any neonate and measurable CRP was present in only a few. No antigen-specific IgG antibodies were elevated in cases compared to controls and total IgG levels were lower. In adjusted models, a 10-unit increase in total IgG yielded an OR = 0.72 (95% CI 0.56, 0.91); a significantly decreasing trend in risk of ASD was observed across increasing exposure quartiles of total IgG (P = 0.01). The finding of lower IgG in cases may indicate maternal immune dysfunction during gestation and/or impaired transplacental transfer of immunoglobulins. Further investigation of IgG levels in newborns and the mechanisms by which they might be associated with ASD are warranted.

This follows on some previous work on maternal antibodies and autism risk. In 2008, UC Davis published: Autism: maternally derived antibodies specific for fetal brain proteins and Johns Hopkins published: Antibodies against fetal brain in sera of mothers with autistic children. These studies looked at the blood sera from mothers of autistic children–sera taken long after the autistic child was born–and found that in some cases there were antibodies in the mothers’ sera against fetal brain proteins. The current study (Grether et al.) looked at blood spots of newborns–samples from the children rather than the mother. They did not find measurable levels of IgM or IgA in the infant’s blood spots. They also did not find c-reactive protein (a response to inflammation).

This study out of France looked at autistic children age 5 and again at age 8. They found that most children’s characteristics were stable, but some did show improvement (e.g. in speech level). What is interesting was the statement that the amount of intervention (hours) was not related to outcome.

Outcome of young children with autism: Does the amount of intervention influence developmental trajectories?

Darrou C, Pry R, Pernon E, Michelon C, Aussilloux C, Baghdadli A.

Montpellier I University, Montpellier III University, France.
Abstract

The study aims were to identify developmental trajectories of young children with autism and investigate their prognostic factors. The participants were 208 children, assessed first at the age of 5 years, followed longitudinally, and reassessed 3 years later. The children’s clinical characteristics and the interventions received were recorded. The results indicated two distinct outcome groups with more stability than change. When changes did occur, they pertained to symptom severity (which decreased) and speech level and adaptive behavior (which improved). A logistic regression analysis pointed out two main risk factors (symptom severity and speech level) and two main protection factors (communication skills and person-related cognition). Surprisingly, the amount of intervention (in terms of number of hours) was not related to outcome.

Given a recent discussion here on LeftBrainRightBrain on genetics, heritability, de-novo mutations and copy number variations (CNV’s), I found the following abstract interesting.

Copy number variation characteristics in subpopulations of patients with autism spectrum disorders.

Bremer A, Giacobini M, Eriksson M, Gustavsson P, Nordin V, Fernell E, Gillberg C, Nordgren A, Uppströmer A, Anderlid BM, Nordenskjöld M, Schoumans J.

Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Abstract

Autism spectrum disorders (ASDs) are a heterogeneous group of disorders with a complex genetic etiology. We used high-resolution whole genome array-based comparative genomic hybridization (array-CGH) to screen 223 ASD patients for gene dose alterations associated with susceptibility for autism. Clinically significant copy number variations (CNVs) were identified in 18 individuals (8%), of which 9 cases (4%) had de novo aberrations. In addition, 20 individuals (9%) were shown to have CNVs of unclear clinical relevance. Among these, 13 cases carried rare but inherited CNVs that may increase the risk for developing ASDs, while parental samples were unavailable in the remaining seven cases. Classification of all patients into different phenotypic and inheritance pattern groups indicated the presence of different CNV patterns in different patient groups. Clinically relevant CNVs were more common in syndromic cases compared to non-syndromic cases. Rare inherited CNVs were present in a higher proportion of ASD cases having first- or second-degree relatives with an ASD-related neuropsychiatric phenotype in comparison with cases without reported heredity (P?=?0.0096). We conclude that rare CNVs, encompassing potential candidate regions for ASDs, increase the susceptibility for the development of ASDs and related neuropsychiatric disorders giving us further insight into the complex genetics underlying ASDs. © 2010 Wiley-Liss, Inc.

I am always very interested in efforts to identify autistic adults. In the following study, from the Netherlands, the ADOS is explored for reliability in an group of “high functioning” autism.

Diagnosing Autism Spectrum Disorders in Adults: the Use of Autism Diagnostic Observation Schedule (ADOS) Module 4.

Bastiaansen JA, Meffert H, Hein S, Huizinga P, Ketelaars C, Pijnenborg M, Bartels A, Minderaa R, Keysers C, de Bildt A.

Social Brain Lab, Department of Neuroscience, University Medical Center, Groningen, Hanzeplein 1, 9700 RB, Groningen, the Netherlands

Abstract

Autism Diagnostic Observation Schedule (ADOS) module 4 was investigated in an independent sample of high-functioning adult males with an autism spectrum disorder (ASD) compared to three specific diagnostic groups: schizophrenia, psychopathy, and typical development. ADOS module 4 proves to be a reliable instrument with good predictive value. It can adequately discriminate ASD from psychopathy and typical development, but is less specific with respect to schizophrenia due to behavioral overlap between autistic and negative symptoms. However, these groups differ on some core items and explorative analyses indicate that a revision of the algorithm in line with Gotham et al. (J Autism Dev Disord 37: 613-627, 2007) could be beneficial for discriminating ASD from schizophrenia.

Lastly, here is an article which I believe may have already been discussed online previously. From PLoS One (which means the article is available free) Which Neurodevelopmental Disorders Get Researched and Why? I don’t think it will come as a surprise to many readers of LeftBrainRightBrain that autism research has seen a particularly large rise in the past decade.

Aim

There are substantial differences in the amount of research concerned with different disorders. This paper considers why.

Methods

Bibliographic searches were conducted to identify publications (1985–2009) concerned with 35 neurodevelopmental disorders: Developmental dyslexia, Developmental dyscalculia, Developmental coordination disorder, Speech sound disorder, Specific language impairment, Attention deficit hyperactivity disorder, Autistic spectrum disorder, Tourette syndrome, Intellectual disability, Angelman syndrome, Cerebral palsy, Cornelia de Lange syndrome, Cri du chat syndrome, Down syndrome, Duchenne muscular dystrophy, Fetal alcohol syndrome, Fragile X syndrome, Galactosaemia, Klinefelter syndrome, Lesch-Nyhan syndrome, Lowe syndrome, Marfan syndrome, Neurofibromatosis type 1, Noonan syndrome, Phenylketonuria, Prader-Willi syndrome, Rett syndrome, Rubinstein-Taybi syndrome, Trisomy 18, Tuberous sclerosis, Turner syndrome, Velocardiofacial syndrome, Williams syndrome, XXX and XYY. A publication index reflecting N publications relative to prevalence was derived.

Results

The publication index was higher for rare than common conditions. However, this was partly explained by the tendency for rare disorders to be more severe.

Interpretation

Although research activity is predictable from severity and prevalence, there are exceptions. Low rates of research, and relatively low levels of NIH funding, characterise conditions that are the domain of a single discipline with limited research resources. Growth in research is not explained by severity, and was exceptionally steep for autism and ADHD.

Residential Proximity to Freeways and Autism in the CHARGE study

16 Dec

The U.C. Davis MIND Institute has an ongoing study to explore autism risk factors due to both genetic and environmental influences: the CHARGE study. The CHARGE study website describes itself as:

CHARGE (Childhood Autism Risks from Genetics and the Environment) was launched in 2003 as a study of 1,000 to 2,000 children with differing patterns of development. The goal is to better understand the causes and contributing factors for autism or developmental delay. Three groups of children are being enrolled in the CHARGE study: children with autism, children with developmental delay who do not have autism and children from the general population. All of them are evaluated for a broad array of exposures and susceptibilities.

A paper from this study was just released. In it, they claim that maternal proximity to freeways might be a risk factor for autism:

Residential Proximity to Freeways and Autism in the CHARGE study.

Volk HE, Hertz-Picciotto I, Delwiche L, Lurmann F, McConnell R.

Abstract

Background: Little is known about environmental causes and contributing factors for autism. Basic science and epidemiological research suggest that oxidative stress and inflammation may play a role in disease development. Traffic-related air pollution, a common exposure with established effects on these pathways, contains substances found to have adverse prenatal effects. Objectives: To examine the association between autism and residence proximity, during pregnancy and near the time of delivery, to freeways and major roadways as a surrogate for air pollution exposure. Methods: Data were from 304 autism cases and 259 typically developing controls enrolled in the Childhood Autism Risks from Genetics and the Environment (CHARGE) Study. The mother’s address recorded on the birth certificate and trimester specific addresses derived from a residential history obtained by questionnaire were geo-coded and measures of distance to freeways and major roads were calculated using ArcGIS software. Logistic regression models compared residential proximity to freeways and major roads for autism cases and typically developing controls. Results: Adjusting for sociodemographic factors and maternal smoking, maternal residence at the time of delivery was more likely be near a freeway (?309 meters) for cases, as compared to controls (odds ratio (OR), 1.86, 95% confidence interval (CI) 1.04-3.45). Autism was also associated with residential proximity to a freeway during the third trimester (OR, 2.22, CI, 1.16-4.42). After adjustment for socio-economic and demographic characteristics, these associations were unchanged. Living near other major roads at birth was not associated with autism. Conclusions: Living near a freeway was associated with autism. Examination of associations with measured air pollutants is needed.

Note: Pubmed lists the affiliation as the University of Southern California. I don’t know if any of these authors are from USC, but I know that CHARGE and Dr. Hertz-Picciotto are with the U.C. Davis MIND Institute.

It is an interesting idea and it will be interesting to see if this result holds up in studies with larger groups.

Girls less likely to be diagnosed with autism than boys

6 Dec

A recent study out in the Disability and Health Journal shows that girls are more likely than boys to remain undiagnosed. The study, by David Mandell‘s group at the University of Pennsylvania, evaluated data from the Autism and Developmental Monitoring Network (ADDM). This is the same group that collects and analyzes data for the CDC’s autism prevalence studies.

Each ADDM study concentrates on children from a specific birth year. In this case, children born in 1994. They review records (medical, educational or both as available) to determine which children meet the criteria for autism. Some children already have a diagnosis of autism in their records. Other children are determined to be autistic via the ADDM review.

Prof. Mandell’s group found that for those with existing diagnoses at the time of review, girls and boys were similar in terms of average age of diagnosis and first age of evaluation. However girls were more likely to be undiagnosed (medical or educational) at the time of the ADDM review.

Here is the abstract.

Sex differences in the evaluation and diagnosis of autism spectrum disorders among children.

Giarelli E, Wiggins LD, Rice CE, Levy SE, Kirby RS, Pinto-Martin J, Mandell D.

Division of Biobehavioral Health Systems, University of Pennsylvania School of Nursing, Philadelphia, PA 19104, USA.
Abstract

BACKGROUND: One of the most consistent features of the autism spectrum disorders (ASDs) is the predominance among males, with approximately four males to every female. We sought to examine sex differences among children who met case definition for ASD in a large, population-based cohort with respect to age at first developmental evaluation, age of diagnosis, influence of cognitive impairment on these outcomes, and sex-specific behavioral characteristics.

METHODS: We conducted a secondary analysis of data collected for a population-based study of the prevalence of ASD. The sample comprised 2,568 children born in 1994 who met the case definition of ASD as established by the Autism and Developmental Disabilities Monitoring (ADDM) Network for ASD surveillance. Children who had a history of developmental disability and behavioral features consistent with the DSM-IV-TR criteria for autistic disorder, Asperger’s disorder, and Pervasive Developmental Disorder-Not Otherwise Specified in existing evaluation records were classified as ASD cases via two paths: streamlined and nonstreamlined. Streamlined reviews were conducted if there was an ASD diagnosis documented in the records. Data were collected in 13 sites across the United States through the ADDM Network, funded by the Centers for Disease Control and Prevention.

RESULTS: Males constituted 81% of the sample. There were no differences by sex in average age at first evaluation or average age of diagnosis among those with an existing documented chart diagnosis of an ASD. Girls were less likely than boys to have a documented diagnosis (odds ratio [OR] = 0.76, p = .004). This analysis was adjusted for cognitive impairment status. In the logistic model, with the interaction term for sex and cognitive impairment, girls with IQ of 70 or less were less likely than boys with IQ of 70 or less to have a documented diagnosis (OR = 0.70, 95% confidence interval [CI] = 0.50-0.97, p = .035). Boys with IQ greater than 70 were less likely than boys with IQ of 70 or less to have a documented diagnosis (OR = 0.60, 95% CI = 0.49-0.74, p < .001). This finding (less likely to have a documented diagnosis) was also true for girls with IQ greater than 70 (OR = 0.45, 95% CI = 0.32-0.66, p < .001). Girls were more likely to have notations of seizure-like behavior (p < .001). Boys were more likely to have notations of hyperactivity or a short attention span and aggressive behavior (p < .01).

CONCLUSIONS: Girls, especially those without cognitive impairment, may be formally identified at a later age than boys. This may delay referral for early intervention. Community education efforts should alert clinicians and parents to the potential of ASDs in boys and girls.

Advancing paternal age and risk of autism

2 Dec

This isn’t the first study to look at paternal age as a possible risk factor for autism but it is, I believe, the first meta-analysis of the subject. The conclusions of the study were:

Based on data from a birth cohort, a family-based study and a meta-analysis, we provide the strongest and most consistent evidence available that advancing paternal age at the time of birth of offspring increases the risk of autism. De novo germline mutations, epigenetic alterations and life course toxic exposure may partly explain the observed association. The evidence is substantial enough to justify a search for the underlying mechanisms in both human and animal models

An interesting conclusion for a few reasons. First and foremost the idea of paternal age being a definite risk factor for autism. Secondly the authors don’t shy away from the idea that ‘life course toxic exposure’ may explain the association. Its not exactly a new observation amongst science (despite what some observers think) but its good to see it placed so clearly amongst the other clear risk factors.

There will be those, I predict, who will have a go at this study for somehow ‘blaming’ fathers/parents. It has happened in the past and will no doubt have the same effect on those who’ll attack this study for their own reasons.

Age of diagnosis for autism: individual and community factors across 10 birth cohorts

6 Nov

Prof. Peter Bearman’s group at Columbia has a new paper out: Age of diagnosis for autism: individual and community factors across 10 birth cohorts.

The study looks at children receiving services from the California Department of Developmental Services (CDDS). The CDDS dataset is not a “census” of autistics in California, but is a registry of those who have sought services, have been identified as autistic and and who have been granted services. Factors which can affect who seeks services for their children, who seeks and how easy it is to identify an autistic child (e.g. access to people who can do the diagosis) will have an effect on who is identified and when that person is identified.

As an aside, I focus on autistic children here because the study does. The authors focused on those identified who were under age 8. They did this to make the comparisons consistent across birth cohorts. For example, one can’t look at 15 year olds born in the year 2000.

Age of diagnosis was taken as age of autism into the entry for the child into the CDDS registry. This can occur either when the child undergoes an intake or a change in the child’s status occurs (say, a diagnosis of autism is given to a child already in the CDDS system)

California statutorily requires that regional centres confirm eligibility for services, including verifying or conferring a diagnosis, within 120 days of intake, so the date at which DDS clinicians either provided or confirmed a first diagnosis of autism is within a few months of caregivers’ initial request for assistance. Combined with the child’s date of birth, we then used the date of entry from the first available CDER to calculate the age of diagnosis. Diagnoses earlier than age 3 years are empirically rare, as infants and toddlers below 36 months with suspected developmental delays and those considered at risk are served by the early start programme.

I don’t have the data, but my very anecdotal and likely biased experience is that currently diagnoses earlier than 36 months are not rare at all.

Prof. Bearman’s group shows that the age of diagnosis steadily dropped during the 1990’s, from 4.4 years of age in 1992 to below 3.4 years of age in 2002. Here’s the figure from the paper (click to enlarge):

Non-White and Hispanic children were diagnosed later. Children of highly educated parents were diagnosed earlier. Both of these effects remained throughout the time span considered (1992-2002). Children of mothers born outside the US and first born children were diagnosed later, but this effect disappeared over time. Children with better communication skills were diagnosed later.

They also found that the age of diagnosis depends on the parents socio-economic status (ses). As one might predict, better off families got diagnoses for their children earlier. Here is the figure showing the trend of age-of-diagnosis vs. birth year for low and high ses:

It is good to see the gap decreasing with time, but it shouldn’t be there at all.

One obvious question that comes up from this study–a question that it can not answer–is how many people are never correctly diagnosed, and what gap might there be in that number based on ses?

The full paper can be found on Prof. Bearman’s team website. Here is the abstract:

Background The incidence of autism rose dramatically between 1992 and 2001, while the age at which children were first diagnosed declined. During this period the size and composition of the autism caseload has changed, but little is known about whether the factors associated with the timing of diagnosis may also have shifted. Using a multilevel analysis strategy, the individual and community-level factors associated with age of diagnosis were modelled across 10 birth cohorts of California children.

Methods Linked birth and administrative records on 17?185 children with diagnoses of autistic disorder born in California between 1992 and 2001 and enrolled with the California Department of Developmental Services (DDS) were analysed. Information on cases, their parents and their residential location were extracted from birth and DDS records. Zip codes of residence were matched to census data to create community-level measures. Multilevel linear models were estimated for each birth cohort, with individual-level effects for sex, race, parental characteristics, poverty status, birth order and symptom expression. At the community level measures of educational and economic composition, local autism prevalence and the presence of a child psychiatrist were included.

Results Children with highly educated parents are diagnosed earlier, and this effect has strengthened over time. There is a persistent gap in the age of diagnosis between high and low socioeconomic status (SES) children that has shrunk but not disappeared over time.

Conclusion Routine screening for autism in early childhood for all children, particularly those of low SES, is necessary to eliminate disparities in early intervention.

Here is the press release for the study.

Autism is diagnosed later for children with less educated parents
A Columbia study, appearing this week in the Journal of Epidemiology and Community Health, has found a gap in age of diagnosis for autism between children of high and low socioeconomic status in California. This gap has become smaller over time, falling from about fourteen months to about six months in a decade, but it remains significant. The strongest factor in this gap was parental education. Children of highly educated parents tend to be diagnosed at earlier ages, and this effect has not diminished over time.

The findings suggest that although the median age of diagnosis for autism has dropped from about four and a half years in the early 1990s to about three and a half in the 2000 birth cohort, there are some groups of children who are still diagnosed late. Diagnosis is the crucial first step to treatment, widely believed to be most effective at younger ages, and even six months may be important at an age when children are developing rapidly. “Our findings point strongly to the idea that some children may be at a great disadvantage when it comes to access to diagnosis and treatment for autism,” said Peter Bearman, the Jonathan Cole Professor of the Social Sciences and principal investigator of the paper. “These delays may have important consequences for later behavioral and cognitive outcomes.”

Autism impairs social interaction and predisposes children to restrictive and repetitive behaviors. Over the past two decades California has witnessed a particularly large spike in autism cases. Between 1992 and 2006, the state’s caseload increased 598 percent. At the same time, the typical age of diagnosis has dropped from school-age to the early pre-school years.

This study was based on 17,185 children with autism born in California from 1992-2001. In addition to looking at characteristics of the children and their parents, from the birth records, the researchers used the zip code at birth and diagnosis to examine the characteristics of the communities in which the children lived.

The researchers found that children born to less-educated mothers, and those whose births were paid for by Medi-Cal (California’s Medicare program) were diagnosed later. In addition, non-White and Hispanic children, and those with mothers born outside the US, showed delayed diagnosis. In the early part of the decade, firstborn children were also diagnosed later, suggesting that parental familiarity with typical child development may have been a factor, however this effect disappeared over time as autism awareness spread.

The kinds of neighborhoods where children lived also mattered, particularly in the early years of the study. In these years, children living in areas that had many children with autism were diagnosed early, which indicates that familiarity with the symptoms of autism may have been important. Children born in neighborhoods with higher property values were also diagnosed earlier. In general though, over time the importance of neighborhood characteristics seems to have diminished, perhaps because autism became more visible and recognized.

“The findings suggest that for many children, increasing awareness of autism and regular screening has succeeded in indentifying cases of autism at earlier ages,” said Christine Fountain, postdoctoral researcher and lead author of the paper. “However we need a better understanding of how information about autism spreads between parents, teachers, and physicians, and how parents marshal their resources to obtain diagnoses and services for their children in a timely way. This will help us to make sure that some children aren’t left undiagnosed and without the help that they need.”

The study was supported by a National Institutes of Health Pioneer Grant, given to scientists pursuing new strategies to improve health, and was conducted through Columbia’s Paul F. Lazarsfeld Center for Social Sciences. More information on this study can be found at http://understandingautism.columbia.edu.

Autism ‘levelling off’?

3 Nov

A new paper in Pediatrics asks:

…whether the increasing prevalence of autism, on the basis of educational data, in Wisconsin between 2002 and 2008 was uniform in all school districts or was greatest in districts with lower baseline (2002) prevalence.

In other words, was there a greater increase in the school districts where the prevalence of autism had previously been lowest? In this ‘catch up’ scenario, there was _still_ no epidemic of autism just a gradual levelling out as the school districts with lower prevalence in 2002 ‘caught up’ with the school districts with the higher prevalence in 2002.

In order to answer this question, the authors

…grouped [the districts] into 8 categories (octiles) according to their baseline prevalence, and prevalence trends were plotted according to octile.

The results were as expected – whilst the _overall_ prevalence increased from 4.9 cases per thousand to 9 cases per thousand, in each different octile, the results were not uniform. If an octile already had near 9 cases per thousand then they increased by a very small amount. If an octile was closer to the 4.9 starting point then they increased over the same amount of time (2002 – 2008) by a much larger amount until both reached the same amount – roughly 1%.

As we know from other studies, a prevalence of 1% seems to be emerging from differing areas of the world as well as different areas of the US. As John Harrington states in a companion commentary, this study shows

There seem to be no “hot spots” or high-risk areas with some ominous environmental toxin that can be postulated; it is more likely that educational services for autism were better coordinated in 1 area versus another.

Autism services are playing catch up in the school system in the US according to this paper. Thats all. Still no epidemic.

Sibling Recurrence and the Genetic Epidemiology of Autism

5 Oct

As if to follow up on the Social Demographic Change and Autism paper we recently discussed here on LeftBrainRightBrain, a new paper on autism recurrence risk in families came out today. Sibling Recurrence and the Genetic Epidemiology of Autism is from a team from the Kennedy Krieger Institute at the Johns Hopkins University. From the abstract I would guess that the study uses the IAN Database.

The authors find about 11% recurrence risk, much higehr than the prevalence of autism (about 1%) and quite similar to that of the Bearman group. Further, the Kennedy Kreiger team find that about 20% of non-autistic siblings have a history of language delay.

Am J Psychiatry. 2010 Oct 1. [Epub ahead of print]
Sibling Recurrence and the Genetic Epidemiology of Autism.

Constantino JN, Zhang Y, Frazier T, Abbacchi AM, Law P.

Departments of Psychiatry and Pediatrics, Washington University School of Medicine, St. Louis; the Center for Autism, Cleveland Clinic, Cleveland; and the Kennedy Krieger Institute, Medical Informatics, Baltimore.
Abstract

Objective: Although the symptoms of autism exhibit quantitative distributions in nature, estimates of recurrence risk in families have never previously considered or incorporated quantitative characterization of the autistic phenotype among siblings. Method: The authors report the results of quantitative characterization of 2,920 children from 1,235 families participating in a national volunteer register, with at least one child clinically affected by an autism spectrum disorder and at least one full biological sibling. Results: A traditionally defined autism spectrum disorder in an additional child occurred in 10.9% of the families. An additional 20% of nonautism-affected siblings had a history of language delay, one-half of whom exhibited autistic qualities of speech. Quantitative characterization using the Social Responsiveness Scale supported previously reported aggregation of a wide range of subclinical (quantitative) autistic traits among otherwise unaffected children in multipleincidence families and a relative absence of quantitative autistic traits among siblings in single-incidence families. Girls whose standardized severity ratings fell above a first percentile severity threshold (relative to the general population distribution) were significantly less likely to have elicited community diagnoses than their male counterparts. Conclusions: These data suggest that, depending on how it is defined, sibling recurrence in autism spectrum disorder may exceed previously published estimates and varies as a function of family type. The results support differences in mechanisms of genetic transmission between simplex and multiplex autism and advance current understanding of the genetic epidemiology of autism spectrum conditions.

Social Demographic Change and Autism: part 2

3 Oct

Prof. Peter Bearman’s group is studying the causes for the rise in autism prevalence, using data from the California Department of Developmental Services. I recently wrote a rather long introduction to their recent paper, Social Demographic Change and Autism.

The study abstract is here:

Social Demographic Change and Autism
Liu K, Zerubavel N, Bearman P.

Abstract

Parental age at child’s birth–which has increased for U.S. children in the 1992-2000 birth cohorts–is strongly associated with an increased risk of autism. By turning a social demographic lens on the historical patterning of concordance among twin pairs, we identify a central mechanism for this association: de novo mutations, which are deletions, insertions, and duplications of DNA in the germ cells that are not present in the parents’ DNA. Along the way, we show that a demographic eye on the rising prevalence of autism leads to three major discoveries. First, the estimated heritability of autism has been dramatically overstated. Second, heritability estimates can change over remarkably short periods of time because of increases in germ cell mutations. Third, social demographic change can yield genetic changes that, at the population level, combine to contribute to the increased prevalence of autism.

They start by noting their group’s previous work which showed an increased risk for autism based on both maternal and paternal age.

There is a strong relationship between parental age and autism. The one study (King et al. 2009) that decomposes maternal and paternal age—and confounding cohort effects— identifies maternal age as riskier than paternal age (using the California data deployed in this analysis).

Relative risks were as high as 1.8. These are not as high as the increased risk for Down Syndrome, which can be 10x higher in older mothers, but it is still a notable effect.

The authors note that parental age has increased notably during the 1990’s, the same time that the “autism epidemic” started.

… the proportion of children born whose parents were age 35 or older at birth increased rapidly: from 24.3% in 1992 to 36.2% in 2000.

Many factors have been identified as correlated to the autism increase. Basically anything that increased over the 1990’s could be argued to be correlated with an increase in autism prevalence. Correlation is not causation, as we hear over and over. One must go beyond correlation in order to claim that there is a real effect.

And Prof. Bearman’s group does go beyond correlation. They look at autism in twins and siblings and show that (1) the concordance is much lower than has been previously reported and (2) the concordance is changing with time. They go into detail on the methods in the paper, including how to determine how many twins were “identical” (monozygotic or MZ) vs. fraternal dizygotic or DZ). Here is the table showing the concordance for twins and sibling pairs from the paper, Casewise and Pairwise concordance numbers are given.

Casewise concordance (Pcw) measures the probability that a co-twin will be affected (with a given disorder), given that the other twin is affected. Pairwise concordance (Ppw) measures the proportion of concordant (both twins are affected) pairs in all pairs with at least one twin who is affected.

Pairwise concordance is what most people think of as concordance.

The pairwise concordance is 40% for MZ (identical) male twins and 50% for female twins. Much lower than the higher values from previous, smaller studies which claimed 36-90% concordance. From the paper from Prof. Bearman’s group:

The Evidence for High Heritability of Autism
To date, the strongest evidence supporting the idea that autism is a genetic disorder arises from twin and family studies. Previous twin studies on full syndrome autism have reported high pairwise concordance rates in identical (MZ) twins (36%–96%) and low concordance rates in fraternal (DZ) twin pairs (0%–31%) (Bailey et al. 1995; Folstein and Rutter 1977; Ritvo et al. 1985; Steffenburg et al. 1989). Because MZ twins share 100% of their genes while DZ twins share only around 50%, a large difference between MZ and DZ concordance rates is regarded as strong evidence for genetic infl uences. The recurrence risk of autism in siblings is reported to range from 3%–9%, which is much higher than the population rate of 10 in 10,000 children (Baird and August 1985; Bolton et al. 1994; Piven et al. 1990; Ritvo et al. 1989).3 Relatives of a child with autism are also more likely to have broadly defined autism spectrum traits than controls (Szatmari et al. 2000).

Low concordance is consistent with another recent study, Genetic variance for autism screening items in an unselected sample of toddler-age twins, from Prof. Goldsmith’s group at U. Wisconsin. The abstract is below:

OBJECTIVE: Twin and family studies of autistic traits and of cases diagnosed with autism suggest high heritability; however, the heritability of autistic traits in toddlers has not been investigated. Therefore, this study’s goals were (1) to screen a statewide twin population using items similar to the six critical social and communication items widely used for autism screening in toddlers (Modified Checklist for Autism in Toddlers); (2) to assess the endorsement rates of these items in a general population; and (3) to determine their heritability.

METHOD: Participants composed a statewide, unselected twin population. Screening items were administered to mothers of 1,211 pairs of twins between 2 and 3 years of age. Twin similarity was calculated via concordance rates and tetrachoric and intraclass correlations, and the contribution of genetic and environmental factors was estimated with single-threshold ordinal models.

RESULTS: The population-based twin sample generated endorsement rates on the analogs of the six critical items similar to those reported by the scale’s authors, which they used to determine an autism threshold. Current twin similarity and model-fitting analyses also used this threshold. Casewise concordance rates for monozygotic (43%) and dizygotic (20%) twins suggested moderate heritability of these early autism indicators in the general population. Variance component estimates from model-fitting also suggested moderate heritability of categorical scores.

CONCLUSIONS: Autism screener scores are moderately heritable in 2- to 3-year-old twin children from a population-based twin panel. Inferences about sex differences are limited by the scarcity of females who scored above the threshold on the toddler-age screener.

Back to Prof. Bearman’s study: their analysis went deeper, including measures of the pairwise concordance for non “identical” twins. Opposite sex twins have a 10% concordance, and same sex twins (dizygotic) have 20% concordance. That gender difference in concordance is quite notable.

The risk of having an autistic child is much higher if one already has an autistic child. The recurrance risk is about 10% for full siblings, 3% for half siblings. These values are quite high considering that the autism (not ASD, but autism) prevalence is less than 1%. The recurrence risk is much higher for siblings of an autistic female than autistic male. Male siblings of a female “proband” have a recurrence risk of 18%. Female siblings of a male “proband” have much lower recurrence risk of 5%.

Prof. Bearman’s group has done what may be a first in concordance studies: analyzed data as a function of birth year. “Temperal concordance”. I.e. they ask the question, does the concordance change with time? The answer, yes.

Here are panels (A) and (B) from Figure 1 of the paper.

Panel (A) shows casewise temporal concordance. Concordance increases for single-sex (SS) twins, and decreases for other-sex (OS) twins during the 1990’s. The authors note this is consistent with a de novo mutation mechanism for increased risk for autism. Panel (B) shows that the average age for the twin parents is also increasing over this time period. From the paper:

In panel B, we report change in mean parental age at twin births, which increases steadily during the same period. Recall that because MZ twins are developed from a single pair of matched egg and sperm cells, any de novo mutations will be found in both twins. In contrast, DZ twins develop from two distinct pairs of egg and sperm cells. Because de novo mutations are rare events, the chance that both DZ twins will share the same de novo mutation is extremely low. If de novo mutations have an increasing causal share in the etiology of autism over time, we should expect an increase in the difference between MZ and DZ concordance rates. One mechanism that accounts for de novo mutations’ increasing share of autism etiology is the rise in parental age over our study period, which is likely to lead to increased mutation rates.

One question that naturally arises in regards to multiple births is the use of assisted reproduction technology (ART). The authors discuss this:

Although the genetic influence on autism has been overestimated, it has increased over time due to non-allelic mechanisms. Although the human gene pool does not change substantially over one or two generations, de novo germ-line mutation rates are much more susceptible to rapid social and/or environmental changes (such as rising parental age), and thus can explain the increase in the heritability of autism. Of importance is the fact that although age of parents at birth of twins was signifi cantly higher in 2000 than in 1992, age of parents at the birth of their second-born did not increase over the same period. Thus, the difference between the trends of OS twin concordance and full-sibling recurrence risk may be associated with age of parents. Since the use of assisted reproductive technologies (ART) is associated with the age of parents and has increased radically over the same time period, ART may be implicated in the increased prevalence of autism. Our data show that the increase in the percentage of children with autism born in multiple births (from 3.6% in 1992 to 5.7% in 2000) exceeded that of the percentage of multiple births in all births in California (from 2.1% in 1992 to 2.9% in 2000). This implication requires future investigation.

The risk of autism is higher with multiple births and increased at a greater rate than the percentage of multiple births in general.

The authors discuss the possibility of prenatal exposures to infection or toxicant or a gene/environment interaction might follow the same trends they observe:

It remains possible that other factors have contributed to the diverging trends in the SS and OS concordance. A virus or a toxicant experienced in utero could yield the results that we observe. Specifically, an increasingly prevalent virus (or toxicant) associated with a small risk of autism would lead to increasing concordance of SS twins (who often share the same placenta) and decreasing concordance of OS twins. Similarly, interactions between genes and an increasingly common environmental trigger could also generate the same pattern. However, we believe that an increase of de novo mutations attributable to rising parental age is more parsimonious given the documented rise in parental age, recent findings that link de novo mutations and autism, and the observed associations between concordance rates and parental age reported in this article.

The authors address one concern that I had in reading the paper: what if some change in the way children are qualified for regional center services changed the characteristics of their population. Or, to put it more simply, are the autistics in 2000 really comparable to those in 1990? Regional center data show a decreasing percentage of children also in the mental retardation and epilepsy categories. Could this have an effect on their results? From the paper:

The temporal concordance trend reported in this article is not predicted by a diagnostic expansion theory. If ascertainment and surveillance dynamics rest behind the increase in SS concordance, we would expect to observe increasing rather than decreasing concordance for OS twin pairs over time. The observation of decreasing concordance over time in OS twins challenges the idea that the results we observe are an artifact of reduction of error in diagnosis as a consequence of enhanced surveillance or clearer understanding of diagnostic markers. First, there is no evidence that diagnostic errors have been reduced; second, if this were the case, we should observe the same effect across all pair types. Finally, increasing ascertainment and surveillance would predict heightened recurrence risk for siblings over time. We do not observe any increase in such risk (chi-square statistics of linear trends in proportion = 1.613; p = .204).

The authors’ concluding paragraph is:

For social scientists, there are three important discoveries. First, we show that a sociological eye on the role of genetics yields the insight that de novo mutations may play a signifi cant role in autism etiology. Only by observing changing patterns of concordance over time—that is, historicizing genetic influences rather than essentializing them—could we find evidence of a new causal mechanism underlying autism. Second, by working with a large population-based data set, versus small clinical samples, we have been able to properly estimate the true heritability of autism. These estimates show that autism is far less heritable than previously thought and consequently, explanations for the precipitous increase in prevalence must turn toward environmental and social dynamics often ignored by the scientific research community. Third, we show that the identification of the mechanisms by which social processes operating at the macro level—in this case, increases in parental age—“get under the skin” and shape health outcomes is a proper social science activity.

This study has the possibility to have a major impact on autism causation research. I would not be surprised at all if this ends up as one of the papers highlighted by the IACC for the year. I’m certain that this paper will be brought up in online discussions for some time to come, what with the very different estimate of twin concordance than previously quoted.

Social Demographic Change and Autism: part 1

3 Oct

I’ve been meaning to blog this for a long time. Ever since it came online, which was months ago. I’ve wanted to do a good job on this paper and so I’ve kept putting it off while I wait for the time to really dig into it. Kev’s recent post about Prof. Bearman got me thinking it is time to get this out. I knew this would be long and it has grown longer than I expected, so I have split the post up. Here are some introductory thoughts. Much as people like to paint me as being in the “genetics” camp, it isn’t really my interest. Someone like Prometheus would do a far better job on an intro and discussion that I can. But in Prom’s absence, I will say what I can.

Prof. Peter Bearman is a researcher at Columbia University. His team has taken a very careful look at the California Department of Developmental Services (CDDS) data and combined this with California birth record data and come up with what are likely some of the best papers to come from those data. The CDDS provides services to the developmentally disabled in California through a series of “Regional Centers”, which are private corporations which administer the state’s funding through largely non-governmental agencies in the state. They have records on the people (consumers) whom they have served over the years and these data include information on how the consumers qualify for services.

There are five eligibility categories for regional center support:

1) Mental Retardation: Significant deficits in general intellectual functioning (generally an IQ of 70 or below) and significant deficits in adaptive functioning.

2) Cerebral Palsy: A neurological condition occurring from birth or early infancy resulting in an inability to voluntarily control muscular activity, and resulting in significant deficits in motor adaptive functioning and or cognitive abilities.

3) Epilepsy: A disorder of the central nervous system in which the major symptoms are seizures. Eligibility is based on a seizure disorder that is uncontrolled or poorly controlled , despite medical compliance and medical intervention.

4) Autism: A syndrome characterized by impairment in social interaction (withdrawal, failure to engage in interaction with peers or adults), delays in both verbal and nonverbal communication skills, deficits in cognitive skills, and impairment in the ability to engage in make-believe play. Individuals may engage in repetitive activities or a limited repertoire of activities.

5) Fifth Condition: This category includes disabling conditions found to be closely related to mental retardation or requiring treatment similar to that required for individuals with mental retardation.

As a side note, a lot of people forget the “Fifth Condition” category. People will say that people with Asperger Syndrome or PDD-NOS don’t qualify for Regional Center services. Well, they don’t under the “autism” category, but they can under the fifth condition if they meet the requirements for a “substantial disability”. But, I am digressing.

The CDDS data have been extensively used to demonstrate the very large increase in autism prevalence that has occurred over the last 20-30 years.
Prof. Bearman’s group has studied the CDDS data and found that some of the increase can be found to attributed to factors such as changes in the way people are diagnosed (diagnostic accretion) and lower ages of identification.

In a recent paper, Social Demographic Change and Autism, Prof. Bearman’s group argues that about 11% of the rise in autism prevalence can be attributed to genetics.

Sorry to give away the conclusion so early but this is going to be long and I know a lot of people won’t read it all.

Genetics is a hot-button issue with a lot of people in the online autism community. Sometimes people will divide the world into two camps: those who believe autism is caused by vaccines and those who believe autism is caused by genetics. It is a major oversimplification but it happens.

Another oversimplification is to confuse genetics and heritability. As in, “I’m not autistic and my wife isn’t autistic, genetics doesn’t account for my kid being autistic”. This is wrong on so many counts. Heritability implies genetics, but not all genetics is heritable.

In high school or even earlier you probably learned about a monk and pea plants and later studies on fruit flies and the color of their eyes. This is Mendelian inheritance. You learned that some traits are recessive and some are dominant.

From this framework, you can’t get a genetic epidemic.

Whenever the argument about genes and changing prevalence comes up, you can be sure someone will eventually bring up Down Syndrome. Down Syndrome is a developmental disability (possibly an example of the sort that comprise the “fifth category” in the DDS). Down Syndrome is genetic. Not always Mendelian inheritance genetic, but genetic all the same.

The risk factors for having a child with Down Syndrome are

1) Advancing maternal age. A woman’s chances of giving birth to a child with Down syndrome increase with age because older eggs have a greater risk of improper chromosome division. By age 35, a woman’s risk of conceiving a child with Down syndrome is 1 in 400. By age 45, the risk is 1 in 35. However, most children with Down syndrome are actually born to women under age 35 because younger women have far more babies.
2) Having had one child with Down syndrome. Typically, a woman who has one child with Down syndrome has about a 1 percent chance of having another child with Down syndrome.
3) Being carriers of the genetic translocation for Down syndrome. Both men and women can pass the genetic translocation for Down syndrome on to their children.

Part 2 and 3 are what we usually think of as “genetic”, as in “Mendalian”. But what about (1) advancing maternal age? A 10 times greater risk for older mothers? Keep in mind, there is a clear genetic difference behind Down Syndrome.

In humans, the egg cells and sperm cells have 23 chromosomes. The rest of your cells normally contain 23 pairs of chromosomes — one from your father and one from your mother. Kids with Down syndrome usually have three copies of chromosome 21 — called trisomy 21 — instead of two copies.

There is a difference, some might call it an error, in the genetic sequence which leads to Down Syndrome. The parents don’t need to have it. It can be genetic and not heritable. Or, at least, not heritable in the way most people think.

Parental age is increasing. We would be seeing an epidemic of Down Syndrome if it weren’t for the genetic test that is available and offered to most pregnant women.

There are already studies out discussing increased risk for having an autistic child with parental age. If parental age is increasing (and it is), why don’t we see an epidemic of autism from this?

Add to this the recent study from the Autism Genome Project (which came out after this paper by Prof. Bearman’s group). That study, and others, are showing that rather than an autism “gene”, that copy number variations (CNVs) may be one source of genetic risk for autism. These are not heritable in the usual sense as usually they exist in the child and not the parent.

According to Prof. Bearman, we are seeing it. It accounts for about 11% of the increase in autism prevalence in the CDDS data. It is a big effect, but small compared to the other factors going on (the other 89%). So without a careful look, one can’t show it.

Prof. Bearman’s group *is* taking a careful look. The result is their paper Social Demographic Change and Autism. There are a lot of very interesting results, like twin concordance being much smaller than has been previously reported. Another recent paper confirms that. Strangely, no one seems to have noticed.

I’ll try to rectify that in the next installment when we look closer at the paper. Until then, here is the abstract:

Parental age at child’s birth—which has increased for U.S. children in the 1992-2000 birth cohorts—is strongly associated with an increased risk of autism. By turning a social demographic lens on the historical patterning of concordance among twin pairs, we identify a central mechanism for this association: de novo mutations, which are deletions, insertions, and duplications of DNA in the germ cells that are not present in the parents’ DNA. Along the way, we show that a demographic eye on the rising prevalence of autism leads to three major discoveries. First, the estimated heritability of autism has been dramatically overstated. Second, heritability estimates can change over remarkably short periods of time because of increases in germ cell mutations. Third, social demographic change can yield genetic changes that, at the population level, combine to contribute to the increased prevalence of autism

Incidence of autism in Berkshire

30 Sep

A Reading Borough Council report has shown that the incidence of autism in a borough of Reading, Tilehurst has increased over a period of eight years (2000 – 2008) from 68 to 186, more than doubling.

Lets put these figures in context of a few things. Firstly, thiomersal. Thiomersal was removed from all UK vaccines in 2004. The average age of autism diagnosis is five and a half (PDF) in the UK. This would mean that if thiomersal caused autism, a significant drop off in autism incidence would have been reported to have been occurring during late 2009 early 2010. This was not reported. This could be because the report did not go beyond 2008 but again there’s no mention of that either and I can’t find the relevant document on the Reading Borough Council website

Secondly, the report seems quite clear to refer to diagnoses of ASD which includes PDD-NOS and Aspergers Syndrome. Kate Manton of Berkshire Autism Society says:

People are being diagnosed much earlier now than they were 10 years ago. Children at two and a half are being diagnosed, if the condition is fairly severe.

Thirty years ago [someone] who was disruptive in class but fairly bright would be called naughty.

All good points and ones which mitigate against the obvious simplistic claims that there is some sort of epidemic of autism. There may well be some sort of ‘epidemic’ of _recognition_ of autism in all its many forms but thats not the same thing at all.

I’m left wishing I could get hold of a copy of the same data that the BBC did so to that end I have requested that the BBC send me a copy of the report. Hopefully they’ll reply.

← Older Entries
Newer Entries →